Okay, you guys know I've been a fan of DIM, and have been using it, for years, but could never quite explain how it works, only pointing out what the following site explains:
- There are two main pathways in the liver for our estrogen to be normally metabolized and excreted. One pathway leads to very good metabolites called 2-hydroxy estrogens. The other pathway leads to bad metabolites called 4 or 16-hydroxy estrogens. DIM stimulates the favorable 2-hydroxy pathway for estrogen metabolism and this is how DIM works to improve our health.
Okay, so we have 2-, 4-, and 16- hydroxyestrogens, all of which are metabolites of estradiol. Turns out these three metabolites are also broken down further (e.g., 2-hydroxyestrogen is made up of 2-hydroxyestrone, which becomes 2-methoxyestrone).
Now consider this comprehensive graph which catalogues most (but not all) of the estrogen metabolites, and remember to scroll right because I couldn't find a way to make the graphic smaller:
So you have estrone and estradiol (17b-estradiol) which go back and forth, and from both (probably more from estradiol) you have three arrows: the left that breaks down to 2-hydroxyestrone, the middle 4-hydroxyestrone, and the right 16a-hydroxyestrone. Remember what the excerpt from the link I posted above said: 2-hydroxyestrogens (which includes the -estrone and -estradiol) are good, and 4- and 16(a)-hydroxyestrones are bad.
Next step. Not included in this graphic is that each arrow stands for an enzyme (which is responsible for the metabolism of one chemical to another), and more specifically a gene that codes for an enzyme: the first arrow stands for a gene/enzyme CYP1A1, the second arrow CYP1B1, and the third arrow I dunno what but it ain't relevant to our discussion. It's very important to grasp this basic idea, because the rest of this post uses these arrows/enzymes as premises from which other conclusions follow. When I mention CYP1A1 being upregulated or increased, this means the first arrow "leaks away" estradiol toward what it points to, 2-hydroxyestrone (which in turn means the rest of the chain below this metabolite is increased). Same thing with CYP1B1. Also important here: because CYP1A1 leads to increasing the pathway that shunts estradiol to 2-hydroxyestrone, and 2-hydroxyestrone is a good, non-carcinogenic estrogen, we want CYP1A1 to be increased; and because CYP1B1 leads to the increase of a bad, carcinogenic estrogen, 4-hydroxyestrone, we want CYP1B1 to be decreased. Also note that any time either of these enzymes, CYP1A1 or 1B1, are increased, this by definition means that 16a-hydroxyestrone is decreased, because the upregulations of CYP1A1/1B1 shunt estrogen away from 16a-hydroxyestrone, which is also considered to be carcinogenic, so we want this to happen. Got it?
Okay, so how does DIM help?
This abstract notes how DIM increases all three relevant CYPs:
- Diindolylmethane (DIM) is an acid-catalyzed condensation product of indole-3-carbinol, a constituent of cruciferous vegetables, and is formed in the stomach. DIM alters estrogen metabolism and inhibits carcinogen-induced mammary tumor growth in rodents. DIM is a weak agonist for the aryl hydrocarbon (Ah) receptor and blocks the effects of estrogens via inhibitory Ah receptor-estrogen receptor cross-talk. DIM and various structural analogs were examined in H295R cells for effects on 3 cytochrome P450 (CYP) enzymes involved in estrogen synthesis and/or metabolism: CYP1A1, CYP1B1, and CYP19 (aromatase). Aromatase activity was measured by conversion of 1 beta-(3)H-androstenedione to estrone and (3)H(2)O. H295R cells were exposed to the test chemicals dissolved in dimethyl sulfoxide for 24 h prior to analyses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (0--30 nM) and DIM (0--10 microM) induced ethoxyresorufin-O-deethylase (EROD) activity, as a measure of CYP1A1 and possibly 1B1 activity, with EC(50) values of about 0.3 nM and 3 microM, respectively. DIM, but not TCDD, induced aromatase activity with an apparently maximal 2-fold increase at 10 microM; higher concentrations of DIM and many of its analogs were cytotoxic. TCDD (30 nM) significantly increased CYP1A1 and 1B1 mRNA levels, but had no effect on mRNA for CYP19. DIM (3 microM) significantly increased mRNA levels for all three CYPS: DIM analogs with substitutions on the 5 and 5' position (3 microM) induced aromatase and EROD activity, together with mRNA levels of CYP1A1, 1B1, and 19; analogs that were substituted on the central carbon of the methane group showed little or no inductive activity toward the CYPS: In conclusion, DIM and several of its analogs appear to induce CYPs via multiple yet distinct pathways in H295R human adrenocortical carcinoma cells.
Whoa, whoa, whoa, wait. DIM increases the activity of the aromatase enzyme CYP19 up to 2-fold? What. The. Heck. This means that DIM is, in a very real sense, an anti-aromatase inhibitor. But why the heck do guys tend to feel positive benefits from it? That would have to do, presumably, with the next point: DIM also increases the activity of CYP1A1 and CYP1B1. But wait! CYP1B1 (look at the graph above) leads to the conversion of estrone/estradiol to 4-hydroxyestrone, which is a bad, cancer-producing estrogen pathway.
So it's not looking great for DIM so far: not only does it (so strangely) seem to increase aromatase (CYP19), but it also increases the proliferation of 4-hydroxyestrogens! But guys feel better on it. Therefore, the effect of DIM on CYP1A1 must explain why guys feel better and counterbalances the negative effects of DIM on aromatase and 4-hydroxyestrogens. Well then!
Dr Crisler (under his old pseudonym, SWALE, on a pretty old Meso-Rx forum post) writes the following:
- I have seen two such studies which showed that DIM stimulated not only the CYP1A1 enzyme, thus increasing 2-OHE, but also the CYP1B1, which is why 4-OHE concentrations rise as well. TMG, or its child, DMG, provides methyl groups, thus helping wash the 4-OHE downstream. IF (and it's a big IF) this is true, in vivo, DIM should not be taken without a methyl donor, and would be especially dangerous in someone with a COMT enzyme deficiency.
So Dr Crisler recommends taking a methyl donor (TMG/betaine is just one option, the others being methylB12, methylfolate, etc.) in order to drain the increase 4-hydroxyestrogens as a result of DIM increasing the CYP1B1 enzyme pathway. Therefore, any guy who takes DIM, assuming Dr Crisler's reasoning is correct (and he's cautious enough to admit that it might not be), should take a methyl donor. But hey, it's good news for the vast majority of people to take methyl donors, so it wouldn't hurt. Moral of the story: take a methyl donor with DIM just to be safe, and if you don't see any positive benefits from taking DIM, maybe adding a methyl donor could help in this regard.
But let's go back to something I've said many times in other places: it seems like a lot of guys who take DIM and get a positive response from it can't really pick up on any noticeable changes in estradiol measured by a lab as a result of taking it. Follow me here: if DIM results in increases in CYP1A1 and CYP1B1, this means that estradiol is "leaked away" to these other pathways which are upregulated, leading to increases in 2- and 4-hydroxyestrogens. But if DIM also increases aromatase activity, perhaps this effect is canceled out (such that increases in aromatase and therefore estradiol are negated by decreases in estradiol from the increase in its conversion to 2- and 4-hydroxyestrones), and this is why we usually don't see decreases in estradiol for guys who take DIM. This also theoretically means that some guys could see decreases in estradiol given their unique biochemistry, and also the reverse by seeing increases in estradiol if the increase in the aromatase enzyme overpowers the increase in the CYP1A1 and CYP1B1 enzymes mentioned above.
So it seems like DIM could be a bit of a wild card, and this could explain its success or lack thereof for different guys: for some guys it increases estradiol (too much aromatase increase and not enough upregulation of CYP1A1 and CYP1B1 to cancel out this effect), others does nothing noticeable to estradiol (aromatase and CYP1A1/1B1 cancel each other out), and others see reductions in estradiol (any increases in aromatase activity are offset by upregulation of CYP1A1/1B1, which "leak away" more estradiol than the increase in aromatase produces).
Okay, case closed, right? Not quite. We have another supplement to consider, indole-3-carbinol, from which DIM is a metabolite. The study titled "Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent." points out the following juicy bit:
- We have focussed our attention on indole-3-carbinol, a compound found in cruciferous vegetables, and its further metabolites in the body, diindolylmethane (DIM) and indolylcarbazole (ICZ), because of its relative safety and multifaceted activities. It has been shown that it induces CyP4501A1, increasing 2-hydroxylation of estrogens, leading to the protective 2-OHE1, and also decreases CyP1B1 sharply, inhibiting 4-hydroxylation of estradiol, thereby decreasing the formation of the carcinogenic 4-OHE1.
Whoa! So somehow Indole-3-carbinol, unlike DIM, sharply decreases CYP1B1, resulting in lower levels of the carcinogenic 4-hydroxyestrogens. Unfortunately, no mention of aromatase (CYP19) was made in the abstract of the article. What this all means is that I-3-C could be advantageous over DIM because it only increases CYP1A1 and decreases CYP1B1, whereas DIM increases both of these enzymes. But, as said above, if you take DIM with a methyl donor, you're going to take care of the increase in 4-hydroxyestrogens from the increase in CYP1B1 DIM offers. Therefore, DIM + methyl donor = I-3-C, and because we don't know of the effects of I-3-C on aromatase, we can't make any conclusions.
So is DIM or Indole-3-carbinol better? That depends on how you take them. If you take DIM by itself, it will increase both 2- and 4-hydroxyestrone pathways, the first being a "good" estrogen pathway and the second being a "bad", carcinogenic pathway. But, per Dr Crisler's statement, if you take a methyl donor (e.g., betaine, methylB12, etc.) you "drain away" any increases in the 4-hydroxyestrone pathway (presumably through increasing the COMT enzyme which converts hydroxyestrogens to methoxyestrogens). DIM also increases aromatase, but we don't know if I-3-C does as well, but seeing how DIM is a metabolite of I-3-C, it's safe to assume that I-3-C probably does increase the aromatase (CYP19) enzyme as well. I-3-C, on the other hand, appears to increase the CYP1A1 pathway (leading to an increase in the "good" estrogens) while sharply reducing the CYP1B1 pathway (leading to an increase in the "bad" carcinogenic estrogens). So basically it seems like taking I-3-C could be less work than taking DIM, which you would have to take with a methyl donor to negate the damage done by increasing the 4-hydroxyestrone pathway. But heck, since we should all be taking methyl donors, there's really no damage done by just taking DIM.
Whoa, science. And while we're talking science, I should note that these differences in DIM and I-3-C could be methodological problems yielding false results; maybe DIM really does (like I-3-C) decrease CYP1B1, but I haven't found the research for this yet.
Nice post Kierkegaard-
It gets at the center of a problem I have been wrestling with-
Managing both the 2-hydroxy and 4-hydroxy estrogen metabolites so that cancer risk is diminished-For a long time I could not crack the methylation of both of these (my 24-hr hormone urine tests consistently poor)
I solved the conversion of the 2-hydroxy estrogens using DIM, and my 2-hydroxy and 2/16 labs looked great for the first time.
At the same time I was managing my overall methylation (as I have a methylation SNP which is impaired). My methylation is doing well now, in part because I am taking 4000mg of TMG/day (some consider 3000mg to me a minimum effective amount).
So I
am one of those folks taking TMG with my DIM. However, I have not been able to see likewise improvements with the 4-hydroxy estrogens, and it confounded me a bit. Clinical evidence re supplementing to manage this estrogen seems to be scarce.
For this reason I was interested in your note about IC3 being a possible solution for managing 4-hydroxy. There are DIM products out there which are combination DIM/IC3 formulations, but I have stayed away from them because the recent science
seems to imply DIM being a safer choice-
http://www.bioresponse.com/Real-Facts-on-Safety-13C-vs-DIM.aspHaving said that, the Bioresponse folks (in the link and who make a very good DIM) are somewhat invested in their analysis.
Still looking for a balanced view...
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